Aspartame consumption during pregnancy impairs placenta growth in mice through sweet taste receptor-reactive oxygen species-dependent pathway

The prevalence of obesity has risen dramatically over recent years, and so has the prevalence of adverse obesity-associated pregnancy outcomes. To combat obesity, the calorie contents of many foods and beverages may be reduced by the use of artificial sweeteners, such as aspartame. However, animal studies suggest that aspartame and its metabolites may exhibit toxicity, and the effects of aspartame on pregnancy are largely unknown. In this study, we treated pregnant mice with aspartame by oral gavage and found that the treatment decreased fasting blood glucose level, whereas systolic blood pressure was elevated. Importantly, the aspartame-treated animals also had low placenta and fetus weights, as well as reduced thickness of the placenta decidua layer. Moreover, aspartame decreased the expression of epithelial-mesenchymal transition proteins and manganese superoxide dismutase (MnSOD) in mouse placentae. In order to clarify the mechanisms though which aspartame affects placenta, we performed experiments on 3A-sub-E trophoblasts. In the cells, aspartame treatments induced cell cycle arrest and reduced the proliferation rate, epithelial-mesenchymal transition, migration activity and invasion activity. We also found that aspartame increased reactive oxygen species (ROS) levels to hyper-activate Akt and downregulate MnSOD expression. Pretreatment with antioxidants or sweet taste receptor inhibitors reversed the effects of aspartame on trophoblast function. We also found that the aspartame metabolite phenylalanine similarly induced ROS production and affected proliferation of trophoblasts. Taken together, our data suggest that aspartame consumption during pregnancy may impact the structure, growth and function of the placenta via sweet taste receptor-mediated stimulation of oxidative stress.(c) 2022 Elsevier Inc. All rights reserved.

Automated summary

The prevalence of obesity and adverse obesity-associated pregnancy outcomes has increased. Aspartame, commonly used as an artificial sweetener, may reduce calorie content in food and drinks, but its effects on pregnancy are largely unknown. In this study, pregnant mice treated with aspartame showed decreased fasting blood glucose level and increased systolic blood pressure. The treated animals had lower placenta and fetus weights, as well as reduced thickness of the placenta decidua layer. Aspartame also affected the expression of certain proteins involved in placental function. In trophoblast cells, aspartame induced cell cycle arrest, reduced proliferation rate and migration activity, and increased oxidative stress. These effects were reversed by antioxidants or sweet taste receptor inhibitors. A metabolite of aspartame, phenylalanine, had similar effects on trophoblasts. Overall, our data suggest that aspartame consumption during pregnancy may impact placental structure, growth, and function through oxidative stress mediated by sweet taste receptors.